Substituted phenoxyethylguanidines



United States Patent SUBSTITUTED PHENUXYETHYLGUANIDINES Frederick Charles Copp and Harold Francis Hudson, London, England, assignors to Burroughs Wellcome & Co.

(U.S.A.) Inc, Tuelrahoe, N.Y., a corporation of New York No Drawing. Filed Jan. 2, 1963, Ser. No. 248,874

4 Claims. (El. 260-501) The present invention relates to alkyl guanidines and to the methods of using them, and is a continuation-inpart of US. application 89,125 filed on February 14, 1961, now U.S. Patent No. 3,099,599.

It has been found that the acid addition salts of the phenoxyalkylguanidines of Formula I have a specific sympatholytic action due to depression of the adrenergic nerve mechanism and not due to a direct antagonism of adrenaline and its congenors, and are free or relatively free from parasympatholytic and parasympathomimetic In Formula (I):

A is an alkylene chain having more than one and less than four carbon atoms;

R is selected from the class consisting of hydrogen and chlorine atoms and a methyl group; and

R is selected from the class consisting of a chlorine atom and methyl and methoxy groups.

The specific sympatholytic action of the acid addition salts of the phenoxyalkylguanidines of Formula I resides in the bases, but the acid must be therapeutically and pharmaceutically acceptable. As sources thereof hydrochloric, hydrobromic and sulphuric acids are satisfactory; however, in certain circumstances organic acids such as lactic, citric and maleic acids oflfer specific advantages because of the physical properties of the salts so formed.

According to the present invention in one aspect, there are provided the acid addition salts of phenoxyalkylguanidines of Formula I.

According to the present invention in another aspect, there is provided a method for the treatment of hypertension which comprises the administration of an acid addition salt of a phenoxyalkylguanidine of Formula I.

The preferred acid addition salts are of 2-(3,5-dimethylphen oxy)-, 2 (3-methylphenoxy)-, 2-(2,4-dichlorophen-oxy)-, 2-(2,6-dichlorophenoxy), 2-(2-chloro-6-methylph-enoxy)- and 2-(2,6-dimethylphenoxy)ethylguanidines and 2-(2,6-dimethylphenoxy)- and 2-(3-methylphenoxy)- propylguanidines. Especially preferred are those of 2-(3- methylphenoxy)- and 2-(2,6 dirnethylphenoxy)ethylguanidines.

The acid addition salts of the phenoxyalkylguanidines of Formula I are synthesised by any method known for synthesising derivatives of guanidine. For example, they are synthesised by the reaction of a guanidine salt with a compound R X, wherein R is a phenoxyalkyl group and X is a reactive atom or group, such as a halogen atom. As a further example, they are synthesised by the reaction of ammonia or an ammonia derivative or a salt thereof with an S-substituted isothiourea or a salt thereof or with a cyanamide; the ammonia derivative may be a primary amine, and the salt of ammonia may be ammonium sulphate, thiocyanate or benzenesulphonate.

The acid addition salts of the phenoxyalkylguanidines of Formula I produced by the above described reactions may be converted by double decomposition either during or after the reactions into salts of other acids. For

3,209,323 Patented Sept. 28, 1965 example, the hydrochlorides may be prepared from the iodides or sulphates by reaction with silver chloride or by warming with methanolic hydrogen chloride.

The acid addition salts of the phenoxyalkylguanidines of Formula I may be presented in pharmaceutical preparations made by any of the methods known to pharmacy. For oral administration, fine powders or granules of the salt may contain diluents and dispersing and surface active agents, and may be presented in a draft or drench in water or in a syrup; in capsules or cachets in the dry state or in a non-aqueous suspension, when a suspending agent may be included; or in a suspension in water or a syrup or an oil; or in a water/oil emulsion, when flavoring, preserving, suspending, thickening and emulsifying agents may be included; the granules or the tablets may be coated. For parenteral administration, the salt may be presented in aqueous or non-aqueous injection solutions which may contain antioxidants, buffers, bacteriostats and solutes which enter the guanidine or salt iostonic with the blood; or in aqueous injection suspensions when suspending and thickening agents may be included; these injection solutions and suspensions are normally in unit dose or multidose containers; extemporaneous injection solutions may be made from sterile powders, granules or tablets which may contain diluents, dispersing and surface active agents, binders and lubricants. The salts may be also presented in suppositories or pessaries by incorporation in a suppository base.

The preferred forms of presentation are tablets and injection solutions. The dose range of the acid addition salt of a phenoxyalkylguanidine of Formula I suitable for administration depends on a number of variable factors such as the activity and toxicity of the particular salt and of the particular base, the mode and frequency of administration of the particular salt, and the method of making the pharmaceutical preparation. The dose range is, however, between 10 mg. and 1.0 g. for continuous medication dosing two or three times a day may be desirable.

The invention will now be described with reference to the following examples in which all temperatures are given in degrees centigrade.

Example 1 A mixture of 3-chloro-4-methylphenol g.) and 1,2-dibromoethane (158.2 g.) in water (60 ml.) was stirred and heated to reflux during the slow dropwise addition of a solution of sodium hydroxide (30.8 g.) in water (140 ml.). Stirring and heating were continued for a total of six hours, and the mixture cooled and extracted exhaustively with ether. The ethereal extract was washed exhaustively with 5 -N-sodiutn hydroxide, dried over potassium carbonate, filtered and evaporated. The residual oil was distilled under reduced pressure to give l-bromo- 2-(3-chloro-4-methylphenoxy)ethane, boiling point 168 171.

A mixture of this ethane (4-0 g.) and potassium phthalimide (29.7 g.) in dimethylformamide (30 ml.) was stirred and heated in an oil-bath. The bath temperature was raised slowly to 140 and maintained at that temperature for 30 minutes. The reaction mixture was poured into water, the mixture allowed to stand at room temperature for one hour, and the precipitated solid removed and dried. One recrystallisation from ethanol and water gave the phthalimide derivative, melting point -133".

A solution of the phthalimide derivative (107 g.) in boiling ethanol (750 ml.) was treated with hydrazine hydrate (38 ml.), and the solution heated to reflux. A voluminous white precipitate formed during the first five minutes of heating. After heating for three hours the mixture was treated cautiously with concentrated hydrochloric acid (80 ml.), heated on a steam-bath for fifteen minutes, and then cooled and filtered. The precipitate was washed well with water and the combined filtrate and washings evaporated under reduced pressure to remove most of the ethanol. The residue was diluted with water, made strongly basic with sodium hydroxide, and the precipitated oil isolated in the usual manner, to give 1-amino-2-(3-chloro 4 methylphenoxy)ethane, boiling point 152-l54/14 mm.

This amine (50 g.) was treated with a solution of S-methylthiouronium sulphate (30 g.) in hot water. The mixture was diluted with ethanol (40 ml.) and the resulting solution heated under reflux for two hours, by which time evolution of methane thiol had ceased. The mixture was allowed to stand at for one hour and the crystalline product was removed, washed with a little water and then with ether, and dried in vacuo. One recrystallisation from ethanol and water gave 2-(3-chloro- 4-methylphenoxy)ethylguanidine sulphate, melting point 196198.

Example 2 Thionyl chloride (26 g.) was slowly added to 2-(3- methylphenoxy)propionic acid (30 g.). After standing at room temperature for 30 minutes, the resulting mixture was heated on a steam-bath for 3 hours and finally distilled in vacuo to give 2-(3-methylphenoxy)propionyl chloride, boiling point 126132/18 mm.

This chloride (30.5 g.) was gradually added to icecooled aqueous ammonia (d=0.880, 155 ml.) during a period of 30 minutes. The final mixture was allowed to warm to room temperature, and the insoluble product was filtered off and recrystallised from isopropanol to give 2-(3-methylphenoxy)propionamide, melting point 132-133. A solution of this amide (9 g.) in dry tetrahydrofuran (200 ml.) was added slowly to a suspension of lithium aluminium hydride (3.8 g.) in dry ether. The final mixture was heated to reflux for 5 /2 hours; after cooling in ice it was treated slowly with ethyl alcohol (5 ml.) and then with N-sodium hydroxide solution. The ethereal layer was decanted off from the inorganic paste, dried over solid potassium hydroxide, filtered and evaporated. The residual 2-(3-methylphenoxy)propylamine was distilled in vacuo, boiling point 128130/17 mm.

This amine (4.8 g.) was added to a solution of S-rnethylthiouronium sulphate (8.1 g.) in water (50 ml.). The resulting mixture was stirred at 45 for 9 hours and at 607 0 for 5 hours; it was then evaporated in vacuo. The residue was extracted with boiling ethanol (25 ml.), and the insoluble portion filtered off. The filtrate was kept at 0 for 48 hours, when a crystalline solid separated. This was collected and recrystallised from ethanol and then from a mixture of ethanol and isopropanol (1:1) to give 2-(3-methylphenoxy)propylguanidine sulphate, melting point 137139.

Example 3 l-amino-2-(3-methylphenoxy)ethane (10 g.) was treated with a solution of S-methylthiouronium sulphate (9.2 g.) in water (65 ml.) and the mixture heated on a steam-bath during 2 /2 hours. The crystalline material which separated on cooling was removed and twice recrystallised from a mixture of ethanol and water to give pure 2-(3-methylphenoxy)ethylguanidine sulphate, melting point 187.

Example 4 l-amino-2-(4-chlorophenoxy)ethane (5.14 g.) was treated with a solution of S-methylthiouronium sulphate (4.17 g.) in water ml.). The mixture was heated on a steam-bath during 2 hours, allowed to cool, and the crystalline reaction product was removed and dried. Two recrystallisations from a mixture of ethanol and water gave pure 2-(4-chlorophenoxy)ethylguanidine sulphate, melting point 226-227".

4 Example 5 A mixture of l-bromo-Z-(2,6-dimethylphenoxy)ethane (16.2 g.) and potassium phthalimide (12.7 g.) in dimethylformamide (14 ml.) was stirred and heated in an oil-bath. The bath temperature was raised slowly to 140 and maintained at this temperature for thirty minutes. The cooled mixture was treated with water (100 ml.) and the precipitated oil extracted with ether. The dried (potassium carbonate) ethereal extract yielded a semi-crystalline mass which crystallised from aqueous ethanol to give the phthalimide derivative.

A solution of the phthalimide derivative (10.2 g.) in ethanol (60 ml.) was treated with hydrazine hydrate (5 ml.) and the mixture heated to reflux for three hours. A voluminous crystalline precipitate formed during the first ten minutes of heating. The cooled mixture was filtered, the residue washed with a little ethanol, and the combined filtrate and washings evaporated under reduced pressure. The residue was distributed between 2 N-hydrochloric acid (30 ml.) and ether (50 ml.), and the ethereal layer was discarded. The acid aqueous portion was made strongly basic with sodium hydroxide, and the precipitated oil isolated with ether in the usual manner, to give 1-amino-2-(2,6-dimethylphenoxy)ethane, boiling point 6162/0.05 mm.

This amine (2.0 g.) was treated with a warm solution of S-methylthiouronium sulphate (1.68 g.) in water (6 ml). The mixture Was warmed gently on a steam-bath, with swirling; methane thiol was evolved and at 50 the mixture became homogeneous. The resulting solution was heated to 70 for a further 1 /2 hours, cooled and the crystalline precipitate removed and dried in vacuo. One recrystallisation from a mixture of water and propan-2-ol gave 2-(2,6-dimethylphenoxy)ethylguanidine sulphate as colourless plates, melting point 235238.

Example 6 2,6-dimethylphenol (183 g.) was added to a solution of sodium (34.5 g.) in ethanol. The resulting darkcoloured mixture was heated on a steam-bath and stirred during the gradual addition of ethyl 2-bromopropionate (271.5 g.) over a period of 90 minutes. The final mixture was heated to reflux for a further hour, cooled and poured into water. The precipitated oil was extracted with ether in the usual way and the ethereal solution washed exhaustively with cold 2 N-sodium hydroxide to remove unchanged, 2,6-dimethylphenol. The residual ethereal solution was dried over potassium carbonate, filtered and evaporated. The residue was distilled in vacuo to give ethyl 2-(2,6-dimethylphenoxy)propionate, boiling point 9091/0.25 mm.

This ester g.) was added slowly to a suspension of lithium aluminium hydride (7.6 g.) in dry ether (300 ml.). The addition was completed in 2 hours, and the final mixture heated to reflux for a further 15 minutes. It was cooled in ice and decomposed with ethyl acetate (25 ml.). Water (25 ml.) was slowly added, followed by concentrated hydrochloric acid (25 ml.). The ethereal layer was decanted from the aqueous portion which was reextracted with fresh ether. The combined ethereal extracts were washed with water, dried over potassium carbonate, filtered and evaporated. The residue was distilled in vacuo to give 2-(2,6-dimethylphenoxy)propan-1-ol.

This alcohol (55.3 g.) was cooled in ice and stirred whilst phosphorus tribromide (49.8 g.) was slowly added. The resulting mixture was stood at room temperature for 48 hours and finally heated on a steam-bath for minutes. It was then cooled and poured on to ice. The precipitated oil was isolated with ether to give l-bromo- 2(2,6 -dimethylphenoxy)propane, boiling point 132- 135 14 mm.

A solution of this bromide (24.3 g.) in alcoholic ammonia (12% w./v.; 250 ml.) was heated in an autoclave for 6 hours (at The reaction mixture was evaporated and excess 5 N-sodium hydroxide added to the residue. The separated oil, 1-amino-2-(2,6-dimethylphenoxy)propane, was isolated with ether and distilled in vacuo, boiling point 126-128/ 13 mm.

This amine (1.8 g.) was added to a solution of S-methylthiouronium sulphate (1.9 g.) in water (10 ml.). The mixture was stirred at 30-40 for 6 hours and fiinally at 60 for one hour. n cooling and scratching the separated oil crystallized to give 2-(2,6-dimethylphenoxy)- propylguanidine sulphate, which was filtered off, washed with a little fresh water and crystallised once from a mixture of ethanol and ether, and then from a mixture of water and ethanol (4:1), melting point ZOO-201.

Example 7 2,6-dichlorophenol (72.5 g.) in ethanol (600' ml.) was added to a solution of sodium (10.4 g.) in ethanol (250 ml.). Ethylene dibromide (187 g.) was added and the resulting mixture heated to reflux for seven hours. The bulk of the ethanol was removed by evaporation under reduced pressure, water added to the residue, and the precipitated oil extracted with ether. The ethereal extract was washed exhaustively with 5 N-sodium hydroxide, dried over anhydrous potassium carbonate, filtered and evaporated. The residual oil Was distilled under reduced pressure to give 1-bromo-2-(2,6-dichlorophenoxy)ethane, boiling point 157-160/11 mm.

A mixture of this ethane (29.7 g.) and potassium phthalimide (18.5 g.) in dimethylformamide ml.) was stirred and heated in an oil-bath. The bath temperature was raised slowly to 140 and maintained at that temperature for thirty minutes. The cooled mixture was treated with water and extracted exhaustively with chloroform. The combined, dried (potassium carbonate) chloroform extracts were evaporated under reduced pressure and the residue recrystallized from a mixture of ethanol and water to give the phthalimide derivative, melting point 12012l.

A solution of the phthalimide derivative (17.0 g.) in hot ethanol 100 ml.) was treated with hydrazine hydrate (1.5 g.) and the mixture heated to reflux for three hours. A voluminous white precipitate formed during the first ten minutes of heating. The mixture was then treated cautiously with concentrated hydrochloric acid until acid to litmus, heated on a steam-bath for fifteen minutes, cooled and filtered. The precipitate was washed with a little water and the combined filtrate and washings evaporated under reduced pressure to remove most of the ethanol. The residue was diluted with water, made strongly basic with sodium hydroxide and the precipitated oil was isolated with ether in the usual manner to give 1- amino-2-(2,6-dichlorophenoxy)ethane, boiling point 140- 142/ 10 mm.

This amine (3.5 g.) was treated with a solution of S- methylthiouronium sulphate (2.35 g.) in warm Water (20 ml.). The mixture was warmed to 70; methane thiol was evolved and after ten minutes the mixture became homogeneous. The resulting solution was maintained at 70 for a total time of two hours, stored in the coldroom overnight, and the crystalline reaction product removed and dried in vacuo. One recrystallisation from a mixture of methanol and water gave pure 2-(2,6-dichlorophenoxyethylguanidine sulphate as colourless prism-s, melting point 199-201".

Example 8 A mixture of 1-bromo-2-(2,4-dichlorophenoxy)ethane (14.27 g.) and potassium phthalimide (9.8 g.) in dimethylformamide (10 ml.) was caused to react as in the second part of Example 7 to give 1-amino-2-(2,4-dichlorophenoxy)ethane, boiling point 163-166/ mm.

This amine (2.06 g.) was treated with a solution of S- methylthiouronium sulphate (1.39 g.) in water (8 ml.) and the resulting mixture heated on a steam-bath during one hour. The crystalline material which separated on cooling was twice recrystallized from ethanol to give pure 2- (2,4-dichlorophenoxy)ethylguanidine sulphate, melting point 217-218.

Example 9 l-amino-Z-(4-chloro-2-methylphenoxy)ethane (6.5 g.) was treated with a solution of S-methylthiouronium sulphate (4.88 g.) in hot water (12 ml.). The mixture was warmed on the steam-bath, treated with ethanol until homogeneous, and then heated under reflux for 2 hours. The product which separated from the cooled mixture had melting point 214216, and was recrystallized twice from a mixture of ethanol and water to give pure 2-(4- chloro-2-methylphenoxy)ethylguanidine sulphate, melting point 221222.

Example 10 A mixture of 2-chloro-6-methylphenol g.) and 1,2-dibromoethane (158 g.) in water ml.) was stirred and heated to reflux during the slow, dropwise addition of a solution of sodium hydroxide (30.8 g.) in water (75 ml.) Stirring and heating were continued for a total of six hours and the reaction mixture was worked up in the usual way to give 1-bromo-2-(2-chloro-6-methylphenoxy)- ethane, boiling point 88-92/0.05 mm.

A mixture of this ethane (41.1 g.) and potassium phthalimide (52.5 g.) in dimethylformamide (40 ml.) was stirred and heated to 150 for 2 hours. The cooled reaction mixture was poured into water and extracted exhaustively with chloroform. The combined, dried chloroform extracts yielded a thick oil which crystallised from ethanol to give the phthalimide derivatives, melting point 92-93". This compound (19 g.) in ethanol (150 ml.), was converted, in the usual way, with hydrazine hydrate (11.4 ml.), to 1-amino-2-(2-chloro-6-methylphenoxy)- ethane, boiling point 146148/ 14 mm.

This amine (4 g.) was treated w-ith a solution of S- methylthiouronium sulphate (3 g.) in hot water (15 ml.) and the mixture warmed on a steam-bath for 70 minutes. The reaction mixture was allowed to stand at 0 for one hour and the resulting crystalline product removed and dried in vacuo; it had melting point 186-193. Two recrystallisations from a mixture of ethanol and water gave pure 2-(2-chloro-6-methylphenoxy)ethylguanidine sulphate, melting point 191-195".

Example 11 1-bromo-2-(2,5-dimethylphenoxy)ethane was converted, essentially as described in the previous examples, to 1-amino-2-(2,5-dimethylphenoxy)ethane, boiling point 133-136/10 mm.

This amine (6.6 g.) by reaction with S-methylthiouro nium sulphate (5.55 g.) in the usual manner, was converted to 2-(2,5-dimethylphenoxy)ethylguanidine sulphate, melting point 226-228, after recrystallisation from a mixture of ethanol and water.

In Examples 12 and 13, the methods employed were essentially as described in the relevant parts of the preceding examples, the physical constants of hitherto undescribed compounds being given.

Example 1 2 1-amino-2-(3,5-dimethylphenoxy)ethane, boiling point 134-136/ 8 mm., obtained from the corresponding brornocompound, was converted to the guanidine. Pure 2-(3,5- dimethylphenoxy)ethylguanidine sulphate had melting point -204", after recrystallisation from a mixture of ethanol and water.

Example 13 1-bromo-3-(3-methylphenoxy)propane, boiling point 144-148/ 10 mm., obtained from the reaction between 3- methylphenol and 1,3-dibromopropane, was converted to 1-amino-3-(3-methylphenoxy)propane, boiling point 139- 140/ 10 mm. This amine reacted with S-methylthiouronium sulphate to give 3-(3-methylphenoxy)propylguanidine sulphate, melting point 152-156 after recrystallisation from a mixture of ethanol and water.

Example 14 Tablets (0.555 g.) containing 2-(3-methylphenoxy)- ethylguanidine sulphate were made by mixing the salt (0.25 g.) in a fine powder with lactose (0.25 g.) and starch (0.05 g.), granulating the mixture with alcohol or alcoholic polyvinyl pyrrolidone or a mixture of equal parts of alcohol and water, drying the granules at 40, adding magnesium stearate (0.005 g.) as a lubricant and compressing the mixture.

Example 15 Tablets (0.505 g.) containing 2-(3-methylphenoxy)- ethylguanidine sulphate were made by granulating the salt (0.5 g.) in a fine powder with equal parts of alcohol and water. Magnesium stearate (0.005 g.) as a lubricant was added, and the mixture compressed directly.

Example 16 Injection solutions containing 2-(3-methylphenoxy)- ethylguanidine sulphate in Water for Injection (0.2 g. per. ml.) were made by autoclaving the solution at 15 lb. steam pressure for 30 minutes in unit dose ampoules or multidose containers. For the latter, the Water for Injection preferably contained benzyl alcohol (1.0%), phenol (0.5%) or chlorocresol (0.1%).

References Cited by the Examiner UNITED STATES PATENTS 2,783,276 2/57 Boatright et al. 260-564 2,836,595 5/58 Parcell 260-268 2,845,459 7/58 Lecher et al. 260-564 2,910,403 10/59 Brendel et al. 167-65 2,928,834 3/60 Shapiro et a1 260-268 2,971,001 2/61 Palopoli et al 260-294.7 2,987,442 6/61 McLean et a1 167-65 OTHER REFERENCES Baltzby et al.: J.A.C.S., v01. 64, pp. 2231-2232 (1942). Kuroda, C. A.: vol. 28, p. 7362 (1934). Kuroda, C. A.: vol. 29, p. 1504 (1935).

CHARLES B. PARKER, Primary Examiner. 

1. A THERAPEUTICALLY ACCEPTABLE ACID ADDITION SALT OF A COMPOUND SELECTED FROM THE CLASS CONSISTING OF 2-(3METHYLPHENOXY)ETHYLGUANIDINE, 2-(2,6-DIMETHYLPHENOXY)ETHYLGUANIDINE AND 2-(2-METHOXYPHENOXY)ETHYLGUANIDINE. 